Polysaccharides are important biological molecules and they have been widely used in the pharmaceutical industry for the prevention and treatment of diseases. For example, capsular polysaccharides have been used for many years in vaccines against capsulated bacteria, such as meningococcus (Neisseria meningitidis), pneumococcus (Streptococcus pneumoniae) and Hib (Haemophilus influenzae type B).
To enhance immunogenicity of capsular polysaccharides, particularly in children, conjugate vaccines were developed. These comprise a capsular saccharide conjugated to a carrier protein [e.g. refs. 1-3]. Conjugation converts T-independent antigens into T-dependent antigens.
The capsular saccharide of Neisseria meningitidis serogroup W135 (“MenW135”) comprises a polymer of sialic acid-galactose disaccharide units:
→4)-D-Neup5Ac(7/90Ac)-α-(2→6)-D-Gal-α-(1→
where “Neu” refers to neuraminic acid, commonly known as sialic acid.
Similarly, the capsular saccharide of Neisseria meningitidis serogroup Y (MenY) comprises a polymer of sialic acid-glucose disaccharide units:
→4)-D-Neup5Ac(7/9OAc)-α-(2→6)-D-Glc-α-(1→
In nature, these capsular saccharides have been found to be O-acetylated at some of the 7 and 9 positions of some of the sialic acid residues. O-acetylation of the W135 saccharide was “reported for the first time” in reference 4, with O-acetylation at the O-7 and O-9 positions being reported. Acetylation at the O-7 and O-9 positions was also seen for the serogroup Y saccharide, although the authors noted that previous work had indicated O-acetylation at O-7, O′-3 or O′-4 positions. Further studies on the O-acetyl content of the saccharides was reported in reference 5.
Reference 5 reports that “there is growing body of evidence that O-acetylation is not important to elicit a protective antibody response” for serogroup W135. In contrast, reference 6 reports that there “is evidence that O-acetylation affects the immunogenicity of polysaccharide vaccines”. On the premise that “O-acetylation of the CPS [capsular polysaccharide] may not be important in eliciting protective immunity”, however, the authors of reference 5 investigated acetylation in serogroups W135 and Y. Among their results, no change in O-acetylation was seen for these two serogroups after storage in basic conditions for 9 days at room temperature.
Reference 7 reported that “the O-acetylation status of the W135 and Y strains” used in tetravalent polysaccharide vaccines “was not reported” previously. The authors went on in reference 8 to report that “little is known about the O-acetylation status of serogroups W135 and Y”, and they stated that further work “may provide useful insights into the optimal vaccine formulation”, although the nature of such further work and the possible insights were not elaborated. Reference 9 reports that the “relevance of O-acetylation to vaccine development remains uncertain” for serogroup W135. Reference 6 agrees that data “on the impact of O-acetylation on immunogenicity of serogroup W-135 or Y polysaccharides are not available yet” (January 2004).
This confusion and lack of information for serogroups W135 and Y contrasts with the two other serogroups for which saccharide vaccines are currently in use. Variation in the O-acetylation of the Neisseria meningitidis serogroup C capsular polysaccharide has been widely reported [10,11], but it does not seem to have any negative impact on immunogenicity, as the Menjugate™ and NeisVac-C™ products are both effective. In contrast, de-O-acetylation of the serogroup A polysaccharide has been associated with a “dramatic reduction in immunogenicity” [12].
It is an object of the invention to provide capsular saccharide derivatives that can be used to make immunogenic compositions, particularly when conjugated to carrier proteins, and particularly for meningococcal serogroups W135 and Y.